Corticotropin releasing factor (herein referred to as CRF), a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin(POMC)--derived peptide secretion from the anterior pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain [W. Vale et al., Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There is also evidence that CRF plays a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors [J. E. Blalock, Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci. 41:527 (1987)].
Clinical data provide evidence that CRF has a role in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and feeding disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF neurons in the central nervous system [for review see E. B. De Souza, Hosp. Practice 23:59 (1988)].
In affective disorder, or major depression, the concentration of CRF is significantly increased in the cerebral spinal fluid (CSF) of drug-free individuals [C. B. Nemeroff et al., Science 226:1342 (1984); C. M. Banki et al., Am. J. Psychiatry 144:873 (1987); R. D. France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al., Biol Psychiatry 25:355 (1989)]. Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF [C. B. Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. In addition, there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v. administered) observed in depressed patients [P. W. Gold et al., Am J. Psychiatry 141:619 (1984); F. Holsboer et al., Psychoneuroendocrinology 9:147 (1984); P. W. Gold et al., New Eng. J. Med. 314:1129 (1986)]. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms seen in human depression [R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the numbers of CRF receptors in brain [Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)].
There has also been a role postulated for CRF in the etiology of anxiety-related disorders. CRF produces anxiogenic effects in animals and interactions between benzodiazepine/non-benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models [D. R. Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J. Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the putative CRF receptor antagonist a-helical ovine CRF (9-41) in a variety of behavioral paradigms demonstrate that the antagonist produces "anxiolytic-like" effects that are qualitatively similar to the benzodiazepines [C. W. Berridge and A. J. Dunn Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71 (1990)]. Neurochemical, endocrine and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics providing further evidence for the involvement of CRF in these disorders. Chlordiazepoxide attenuates the "anxiogenic" effects of CRF in both the conflict test [K. T. Britton et al., Psychopharmacology 86:170 (1985); K. T. Britton et al., Psychopharmacology 94:306 (1988)] and in the acoustic startle test [N. R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. The benzodiazepine receptor antagonist (Ro15-1788), which was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner while the benzodiazepine inverse agonist (FG7142) enhanced the actions of CRF [K. T. Britton et al., Psychopharmacology 94:306 (1988)].
The mechanisms and sites of action through which the standard anxiolytics and antidepressants produce their therapeutic effects remain to be elucidated. It has been hypothesized however, that they are involved in the suppression of the CRF hypersecretion that is observed in these disorders. Of particular interest is that preliminary studies examining the effects of a CRF receptor antagonist (.alpha.-helical CRF.sub.9-41) in a variety of behavioral paradigms have demonstrated that the CRF antagonist produces "anxiolytic-like" effects qualitatively similar to the benzodiazepines [for review see G. F. Koob and K. T. Britton, In: Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E. B. De Souza and C. B. Nemeroff eds., CRC Press p221 (1990)].
Several publications describe corticotropin releasing factor antagonist compounds and their use to treat psychiatric disorders and neurological diseases. Examples of such publications include DuPont Merck PCT application U.S. Ser. No. 94/11050, Pfizer WO 95/33750, Pfizer WO 95/34563, Pfizer WO 95/33727 and Pfizer EP 0778 277 A1.
Insofar as is known, [1,5-a]-pyrazolo-1,3,5-triazines, [1,5-a]-1,2,3-triazolo-1,3,5-triazines, [1,5-a]-pyrazolo-pyrimidines and [1,5-a]-1,2,3-triazolo-pyrimidines, have not been previously reported as corticotropin releasing factor antagonist compounds useful in the treatment of psychiatric disorders and neurological diseases. However, there have been publications which teach some of these compounds for other uses.
For instance, EP 0 269 859 (Ostuka, 1988) discloses pyrazolotriazine compounds of the formula ##STR2##
where R.sup.1 is OH or alkanoyl, R.sup.2 is H, OH, or SH, and R.sup.3 is an unsaturated heterocyclic group, naphthyl or substituted phenyl, and states that the compounds have xanthine oxidase inhibitory activity and are useful for treatment of gout. PA1 where A is CH or N, R.sup.0 and R.sup.3 are H or alkyl, and R.sup.1 and R.sup.2 are H, alkyl, alkoxyl, alkylthio, nitro, etc., and states that the compounds inhibit androgen and are useful in treatment of benign prostatic hypertrophy and prostatic carcinoma. PA1 where R1 is CH.sub.3, C.sub.2 H.sub.5 or C.sub.6 H.sub.5, X is H, C.sub.6 H.sub.5, m-CH.sub.3 C.sub.6 H.sub.4, CN, COOEt, Cl, I or Br, Y is H, C.sub.6 H.sub.5, o-CH.sub.3 C.sub.6 H.sub.4, or p-CH.sub.3 C.sub.6 H.sub.4, and Z is OH, H, CH.sub.3, C.sub.2 H.sub.5, C.sub.6 H.sub.5, n-C.sub.3 H.sub.7, i-C.sub.3 H.sub.7, SH, SCH.sub.3, NHC.sub.4 H.sub.9, or N(C.sub.2 H.sub.5).sub.2, and states that the compounds are c-AMP phosphodiesterase inhibitors useful as bronchodilators. PA1 where R.sup.1 is H or alkyl, R.sup.2 is H or alkyl, R.sup.3 is H, alkyl, alkanoyl, carbamoyl, or lower alkylcarbamoyl, and R is pyridyl, pyrimidinyl, or pyrazinyl, and states that the compounds are useful as bronchodilators. PA1 where R is lower alkoxy, and teaches that the compounds are xanthine oxidase inhibitors and are useful for treatment of gout. PA1 where X is O or S, Ar is a phenyl, naphthyl, pyridyl or thienyl group, R.sub.6 -R.sub.8 are H, alkyl, etc., and R.sub.9 is H, alkyl, phenyl, etc. The patent states that the compounds are useful as herbicides and plant growth regulants. PA1 where A can be N, B can be CR.sub.3, R.sub.3 can be phenyl or substituted phenyl, etc., R is --N(R.sub.4)SO.sub.2 R.sub.5 or --SO.sub.2 N(R.sub.6)R.sub.7 and R.sub.1 and R.sub.2 can be taken together to form ##STR9## PA1 where Z is H, OH, CH.sub.3, C.sub.2 H.sub.5, C.sub.6 H.sub.5, n-C.sub.3 H.sub.7, iso-C.sub.3 H.sub.7, SH, SCH.sub.3, NH(n-C.sub.4 H.sub.9), or N(C.sub.2 H.sub.5).sub.2, R is H or CH.sub.3, and R.sub.1 is CH.sub.3 or C.sub.2 H.sub.5. The reference lists eight therapeutic areas where inhibitors of cAMP phosphodiesterase could have utility: asthma, diabetes mellitus, female fertility control, male infertility, psoriasis, thrombosis, anxiety, and hypertension. PA1 where Q is carbonyl or sulfonyl, n is 0 or 1, A is a single bond, alkylene or alkenylene, R.sup.1 is H, alkyl, etc., R.sup.2 is naphthyl, cycloalkyl, heteroaryl, substituted phenyl or phenoxy, R.sup.3 is H, alkyl or phenyl, R.sup.4 is H, alkyl, alkoxycarbonyl, phenylalkyl, optionally phenylthio-substituted phenyl, or halogen, R.sup.5 and R.sup.6 are H or alkyl. PA1 where R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are H, carboxyl, alkoxycarbonyl, optionally substituted alkyl, cycloalkyl, or phenyl, R.sub.5 is SR.sub.6 or NR.sub.7 R.sub.8, R.sub.6 is pyridyl or optionally substituted phenyl, and R.sub.7 and R.sub.8 are H or optionally substituted phenyl. PA1 where R can be phenyl, substituted phenyl or pyridyl, and their use to treat gout, based on their ability to inhibit xanthine oxidase. PA1 where R.sup.1 is CF.sub.3, C.sub.2 F.sub.5, or C.sub.6 H.sub.4 F, and R.sup.2 is CH.sub.3, C.sub.2 H.sub.5, CF.sub.3, or C.sub.6 H.sub.4 F. PA1 where R is NH2 or OH and Ar is 4-phenyl-3-cyano-2-aminopyrid-2-yl. PA1 A is N or CR; PA1 Z is N or CR.sup.2 ; PA1 Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl, 3,4-dihydro-1,2-benzopyranyl, tetralinyl, each Ar optionally substituted with 1 to 5 R.sup.4 groups and each Ar is attached to an unsaturated carbon atom; PA1 R is independently selected at each occurrence from H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.7 cycloalkylalkyl, halo, CN, C.sub.1 -C.sub.4 haloalkyl; PA1 R.sup.1 is independently selected at each occurrence from H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, halo, CN, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.12 hydroxyalkyl, C.sub.2 -C.sub.12 alkoxyalkyl, C.sub.2 -C.sub.10 cyanoalkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.l0 cycloalkylalkyl, NR.sup.9 R.sup.10, C.sub.1 -C.sub.4 alkyl-NR.sup.9 R.sup.10, NR.sup.9 COR.sup.10, OR.sup.11, SH or S(O).sub.n R.sup.12 ; PA1 R.sup.2 is selected from H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl, C.sub.1 -C.sub.4 hydroxyalkyl, halo, CN, --NR.sup.6 R.sup.7, NR.sup.9 COR.sup.10, --NR.sup.6 S(O).sub.n R.sup.7, S(O).sub.n NR.sup.6 R.sup.7, C.sub.1 -C.sub.4 haloalkyl, --OR.sup.7, SH or --S(O).sub.n R.sup.12 ; PA1 R.sup.3 is selected from: PA1 R.sup.4 is independently selected at each occurrence from: PA1 R.sup.6 and R.sup.7, R.sup.6a and R.sup.7a are independently selected at each occurrence from: PA1 alternatively, NR.sup.6 R.sup.7 and NR.sup.6a R.sup.7a are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C.sub.1 -C.sub.4 alkyl groups; PA1 R.sup.8 is independently selected at each occurrence from H or C.sub.1 -C.sub.4 alkyl; PA1 R.sup.9 and R.sup.10 are independently selected at each occurrence from H, C.sub.1 -C.sub.4 alkyl, or C.sub.3 -C.sub.6 cycloalkyl; PA1 R.sup.11 is selected from H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 haloalkyl, or C.sub.3 -C.sub.6 cycloalkyl; PA1 R.sup.12 is C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 haloalkyl; PA1 R.sup.13 is selected from C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.2 -C.sub.8 alkoxyalkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, aryl, aryl(C.sub.1 -C.sub.4 alkyl)-, heteroaryl or heteroaryl(C.sub.1 -C.sub.4 alkyl)-; PA1 R.sup.14 is selected from C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, C.sub.3 -C.sub.10 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, or C.sub.4 -C.sub.12 cycloalkylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.15, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.15, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.15, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, and C.sub.1 -C.sub.6 alkylthio, C.sub.1 -C.sub.6 alkylsulfinyl and C.sub.1 -C.sub.6 alkylsulfonyl; PA1 R.sup.15 and R.sup.16 are independently selected at each occurrence from H, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.4 -C.sub.16 cycloalkylalkyl, except that for S(O).sub.n R.sup.15, R.sup.15 cannot be H; PA1 aryl is phenyl or naphthyl, each optionally substituted with 1 to 5 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.15, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.15, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.15, NR.sup.16 R.sup.15, and CONR.sup.16 R.sup.15 ; PA1 heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, 2,3-dihydrobenzothienyl or 2,3-dihydrobenzofuranyl, each being optionally substituted with 1 to 5 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.15, --COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.15, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.15, NR.sup.16 R.sup.15, and CONR.sup.16 R.sup.15 ; PA1 heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 5 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.15, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.15, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.15, NR.sup.15 R.sup.16, and CONR.sup.16 R.sup.15 ; PA1 n is independently at each occurrence 0, 1 or 2, PA1 A is N or CR; PA1 Z is N or CR.sup.2 ; PA1 Ar is-selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl, 3,4-dihydro-1,2-benzopyranyl, tetralinyl, each Ar optionally substituted with 1 to 5 R.sup.4 groups and each Ar is attached to an unsaturated carbon atom; PA1 R is independently selected at each occurrence from H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.7 cycloalkylalkyl, halo, CN, C.sub.1 -C.sub.4 haloalkyl; PA1 R.sup.1 is independently selected at each occurrence from H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, halo, CN, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.12 hydroxyalkyl, C.sub.2 -C.sub.12 alkoxyalkyl, C.sub.2 -C.sub.10 cyanoalkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl, NR.sup.9 R.sup.10, C.sub.1 -C.sub.4 alkyl-NR.sup.9 R.sup.10, NR.sup.9 COR.sup.10, OR.sup.11, SH or S(O).sub.n R.sup.12 ; PA1 R.sup.2 is selected from H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl, C.sub.1 -C.sub.4 hydroxyalkyl, halo, CN, --NR.sup.6 R.sup.7, NR.sup.9 COR.sup.10, --NR.sup.6 S(O).sub.n R.sup.7, S(O).sub.n NR.sup.6 R.sup.7, C.sub.1 -C.sub.4 haloalkyl, --OR.sup.7, SH or --S(O).sub.n R.sup.12 ; PA1 R.sup.3 is selected from: PA1 R.sup.4 is independently selected at each occurrence from: C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, NO.sub.2, halo, CN, C.sub.1 -C.sub.4 haloalkyl, NR.sup.6 R.sup.7, NR.sup.8 COR.sup.7, NR.sup.8 CO.sub.2 R.sup.7, COR.sup.7, OR.sup.7, CONR.sup.6 R.sup.7, CO(NOR.sup.9)R.sup.7, CO.sub.2 R.sup.7, or S(O).sub.n R.sup.7, where each such C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.3 -C.sub.6 cycloalkyl and C.sub.4 -C.sub.12 cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.4 alkyl, NO.sub.2, halo, CN, NR.sup.6 R.sup.7, NR.sup.8 COR.sup.7, NR.sup.8 CO.sub.2 R.sup.7, COR.sup.7 OR.sup.7, CONR.sup.6 R.sup.7, CO.sub.2 R.sup.7, CO(NOR.sup.9)R.sup.7, or S(O).sub.n R.sup.7 ; PA1 R.sup.6 and R.sup.7, R.sup.6a and R.sup.7a are independently selected at each occurrence from: PA1 alternatively, NR.sup.6 R.sup.7 and NR.sup.6a R.sup.7a are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C.sub.1 -C.sub.4 alkyl groups; PA1 R.sup.8 is independently selected at each occurrence from H or C.sub.1 -C.sub.4 alkyl; PA1 R.sup.9 and R.sup.10 are independently selected at each occurrence from H, C.sub.1 -C.sub.4 alkyl, or C.sub.3 -C.sub.6 cycloalkyl; PA1 R.sup.11 is selected from H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 haloalkyl, or C.sub.3 -C.sub.6 cycloalkyl; PA1 R.sup.12 is C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 haloalkyl; PA1 R.sup.13 is selected from C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.2 -C.sub.8 alkoxyalkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, aryl, aryl(C.sub.1 -C.sub.4 alkyl)-, heteroaryl or heteroaryl(C.sub.1 -C.sub.4 alkyl)-; PA1 R.sup.14 is selected from C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, C.sub.3 -C.sub.10 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, or C.sub.4 -C.sub.12 cycloalkylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.15, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.15, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.15, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, and C.sub.1 -C.sub.6 alkylthio, C.sub.1 -C.sub.6 alkylsulfinyl and C.sub.1 -C.sub.6 alkylsulfonyl; PA1 R.sup.15 and R.sup.16 are independently selected at each occurrence from H, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.4 -C.sub.16 cycloalkylalkyl, except that for S(O).sub.n R.sup.15, R.sup.15 cannot be H; PA1 aryl is phenyl or naphthyl, each optionally substituted with 1 to 5 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.15, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.15, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.15, NR.sup.16 R.sup.15, and CONR.sup.16 R.sup.15 ; PA1 heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, 2,3-dihydrobenzothienyl or 2,3-dihydrobenzofuranyl, each being optionally substituted with 1 to 5 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.15, --COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.15, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.15, NR.sup.16 R.sup.15, and CONR.sup.16 R.sup.15 ; PA1 heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 5 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.15, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.15, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.15, NR.sup.15 R.sup.16, and CONR.sup.16 R.sup.15 ; PA1 n is independently at each occurrence 0, 1 or 2, with the provisos that: PA1 H, PA1 C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, C.sub.3 -C.sub.10 alkynyl, C.sub.1 -C.sub.10 haloalkyl with 1-10 halogens, C.sub.2 -C.sub.8 alkoxyalkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, C.sub.5 -C.sub.10 cycloalkenyl, or C.sub.6 -C.sub.14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.13, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.13, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, aryl, heteroaryl or heterocyclyl, PA1 aryl, aryl(C.sub.1 -C.sub.4 alkyl)-, heteroaryl, heteroaryl(C.sub.1 -C.sub.4 alkyl)-, heterocyclyl or heterocyclyl(C.sub.1 -C.sub.4 alkyl)-; and PA1 H, PA1 C.sub.5 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, C.sub.3 -C.sub.10 alkynyl, C.sub.1 -C.sub.10 haloalkyl with 1-10 halogens, C.sub.2 -C.sub.8 alkoxyalkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, C.sub.5 -C.sub.10 cycloalkenyl, or C.sub.6 -C.sub.14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.13, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.13, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, aryl, heteroaryl or heterocyclyl, PA1 aryl, aryl(C.sub.1 -C.sub.4 alkyl), heteroaryl, heteroaryl(C.sub.1 -C.sub.4 alkyl), heterocyclyl or heterocyclyl(C.sub.1 -C.sub.4 alkyl); PA1 C.sub.1 -C.sub.4 alkyl or C.sub.3 -C.sub.6 cycloalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.13, --COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.13, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, aryl, heteroaryl or heterocyclyl, and PA1 aryl or heteroaryl. PA1 H, PA1 C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, C.sub.3 -C.sub.10 alkynyl, C.sub.1 -C.sub.10 haloalkyl with 1-10 halogens, C.sub.2 -C.sub.8 alkoxyalkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, C.sub.5 -C.sub.10 cycloalkenyl, or C.sub.6 -C.sub.14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.13, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.13, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, aryl, heteroaryl or heterocyclyl, PA1 aryl, aryl(C.sub.1 -C.sub.4 alkyl), heteroaryl, heteroaryl(C.sub.1 -C.sub.4 alkyl), heterocyclyl or heterocyclyl(C.sub.1 -C.sub.4 alkyl); PA1 C.sub.1 -C.sub.4 alkyl and each such C.sub.1 -C.sub.4 alkyl is substituted with 1-3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.13, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.13, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, aryl, heteroaryl or heterocyclyl. PA1 C.sub.3 -C.sub.6 cycloalkyl, each such C.sub.3 -C.sub.6 cycloalkyl optionally substituted with 1-3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.13, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.13, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, aryl, heteroaryl or heterocyclyl, PA1 aryl, PA1 heteroaryl or PA1 heterocyclyl, PA1 H, PA1 C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, C.sub.3 -C.sub.10 alkynyl, C.sub.1 -C.sub.10 haloalkyl with 1-10 halogens, C.sub.2 -C.sub.8 alkoxyalkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, C.sub.5 -C.sub.10 cycloalkenyl, or C.sub.6 -C.sub.14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.13, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.13, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, aryl, heteroaryl or heterocyclyl, PA1 aryl, aryl(C.sub.1 -C.sub.4 alkyl)-, heteroaryl, heteroaryl(C.sub.1 -C.sub.4 alkyl), heterocyclyl or heterocyclyl(C.sub.1 -C.sub.4 alkyl); PA1 H, PA1 C.sub.5 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, C.sub.3 -C.sub.10 alkynyl, C.sub.1 -C.sub.10 haloalkyl with 1-10 halogens, C.sub.2 -C.sub.8 alkoxyalkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, C.sub.5 -C.sub.10 cycloalkenyl, or C.sub.6 -C.sub.14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.13, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.13, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, aryl, heteroaryl or heterocyclyl, PA1 aryl, aryl(C.sub.1 -C.sub.4 alkyl), heteroaryl, heteroaryl(C.sub.1 -C.sub.4 alkyl), heterocyclyl or heterocyclyl(C.sub.1 -C.sub.4 alkyl), PA1 C.sub.1 -C.sub.4 alkyl or C.sub.3 -C.sub.6 cycloalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.13, --COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.13, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, aryl, heteroaryl or heterocyclyl, and PA1 aryl or heteroaryl. PA1 C.sub.1 -C.sub.4 alkyl, each such C.sub.1 -C.sub.4 alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.13, --COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.13, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, aryl, heteroaryl or heterocyclyl. PA1 H, PA1 C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, C.sub.3 -C.sub.10 alkynyl, C.sub.1 -C.sub.10 haloalkyl with 1-10 halogens, C.sub.2 -C.sub.8 alkoxyalkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, C.sub.5 -C.sub.10 cycloalkenyl, or C.sub.6 -C.sub.14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.13, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.13, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, aryl, heteroaryl or heterocyclyl, PA1 aryl, aryl(C.sub.1 -C.sub.4 alkyl), heteroaryl, heteroaryl(C.sub.1 -C.sub.4 alkyl), heterocyclyl or heterocyclyl(C.sub.1 -C.sub.4 alkyl); PA1 C.sub.1 -C.sub.4 alkyl and each such C.sub.1 -C.sub.4 alkyl is substituted with 1--3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.13, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.13, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, aryl, heteroaryl or heterocyclyl. PA1 C.sub.3 -C.sub.6 cycloalkyl, each such C.sub.3 -C.sub.6 cycloalkyl optionally substituted with 1-3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.13, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.13, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, aryl, heteroaryl or heterocyclyl, PA1 aryl, PA1 heteroaryl or PA1 heterocyclyl, PA1 Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R.sup.4 substituents, PA1 R.sup.3 is NR.sup.6a R.sup.7a or OR.sup.7 and PA1 R.sup.1 and R.sup.2 are independently selected from H, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl. PA1 H, PA1 C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, C.sub.3 -C.sub.10 alkynyl, C.sub.1 -C.sub.10 haloalkyl with 1-10 halogens, C.sub.2 -C.sub.8 alkoxyalkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, C.sub.5 -C.sub.10 cycloalkenyl, or C.sub.6 -C.sub.14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.13, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.13, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, aryl, heteroaryl or heterocyclyl, PA1 aryl, aryl(C.sub.1 -C.sub.4 alkyl)-, heteroaryl, heteroaryl(C.sub.1 -C.sub.4 alkyl), heterocyclyl or heterocyclyl(C.sub.1 -C.sub.4 alkyl); PA1 H, PA1 C.sub.5 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, C.sub.3 -C.sub.10 alkynyl, C.sub.1 -C.sub.10 haloalkyl with 1-10 halogens, C.sub.2 -C.sub.8 alkoxyalkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, C.sub.5 -C.sub.10 cycloalkenyl, or C.sub.6 -C.sub.14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.13, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.13, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, aryl, heteroaryl or heterocyclyl, PA1 aryl, aryl(C.sub.1 -C.sub.4 alkyl), heteroaryl, heteroaryl(C.sub.1 -C.sub.4 alkyl), heterocyclyl or heterocyclyl(C.sub.1 -C.sub.4 alkyl), PA1 C.sub.1 -C.sub.4 alkyl or C.sub.3 -C.sub.6 cycloalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.13, --COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.13, NR.sup.8 COR.sup.15, N(COR.sup.15)2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, aryl, heteroaryl or heterocyclyl, and PA1 aryl or heteroaryl. PA1 C.sub.1 -C.sub.4 alkyl, each such C.sub.1 -C.sub.4 alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.13, --COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.13, NR.sup.8 COR.sup.15, N(COR.sup.15)2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, aryl, heteroaryl or heterocyclyl. PA1 H, PA1 C.sub.1 --C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, C.sub.3 -C.sub.10 alkynyl, C.sub.1 -C.sub.10 haloalkyl with 1-10 halogens, C.sub.2 -C.sub.8 alkoxyalkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, C.sub.5 -C.sub.10 cycloalkenyl, or C.sub.6 -C.sub.14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.13, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.13, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, aryl, heteroaryl or heterocyclyl, PA1 aryl, aryl(C.sub.1 -C.sub.4 alkyl), heteroaryl, heteroaryl(C.sub.1 -C.sub.4 alkyl), heterocyclyl or heterocyclyl(C.sub.1 -C.sub.4 alkyl); PA1 C.sub.1 -C.sub.4 alkyl and each such C.sub.1 -C.sub.4 alkyl is substituted with 1-3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O)nR.sup.13, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.13, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, aryl, heteroaryl or heterocyclyl. PA1 C.sub.3 -C.sub.6 cycloalkyl, each such C.sub.3 -C.sub.6 cycloalkyl optionally substituted with 1-3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O)nR.sup.13, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.13, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, aryl, heteroaryl or heterocyclyl, PA1 aryl, PA1 heteroaryl or PA1 heterocyclyl, PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(n-Pr).sub.2, R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --N(Et)(n-Bu), R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --(n-Pr) (CH.sub.2 cPr), R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --N(CH.sub.2 CH.sub.2 OMe).sub.2, R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(Et) (n-Bu), R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(Et) (CH.sub.2 OMe), R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(CH.sub.2 OMe).sub.2, R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --N(Et).sub.2, R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(CH.sub.2 OEt).sub.2, R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(Et).sub.2, R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --N(Me) (Ph), R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --N(n-Pr).sub.2, R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(Et) (n-Pr), R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(CH.sub.2 OMe).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is Me; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(CH.sub.2 OMe).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --N(CH.sub.2 CH.sub.2 OMe).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(Et) (CH.sub.2 OMe), R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(Et).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --OEt, R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --N(Et).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --N(CH.sub.2 CN).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(Me) (CH.sub.2 OMe), R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --OCH(Et) (CH.sub.2 OMe), R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --N(n-Pr) (CH.sub.2 cPr), R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(Me) (CH.sub.2 N(Me)2), R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 compound of Formula (50) wherein R.sup.3 is --N(cPr) (CH.sub.2 CH.sub.2 CN), R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --N(n-Pr) (CH.sub.2 CH.sub.2 CN), R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4 d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --N(n-Bu) (CH.sub.2 CN), R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(Et) (CH.sub.2 OMe), R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is Me; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(Et).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is Me; PA1 a compound of Formula (50) wherein R.sup.3 is --N(CH.sub.2 CH.sub.2 OMe).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is Me; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(CH.sub.2 OMe).sub.2, R.sup.4a is Br, R.sup.4b is H, R.sup.4c is OMe, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(Et) (CH.sub.2 OMe), R.sup.4a is Br, R.sup.4b is H, R.sup.4c is OMe, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --N(Et).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is Me; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(CH.sub.2 OEt).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is Me; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(CH.sub.2 CH.sub.2 OMe) (CH.sub.2 OMe).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is Me; PA1 a compound of Formula (50) wherein R.sup.3 is morpholino, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --N(CH.sub.2 CH.sub.2 OMe).sub.2, R.sup.4a is Br, R.sup.4b is H, R.sup.4c is OMe, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(Et).sub.2, R.sup.4a is Br, R.sup.4b is H, R.sup.4c is OMe, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --N(Et).sub.2, R.sup.4a is Br, R.sup.4b is H, R.sup.4c is OMe, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NH(c-Pr), R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(CH.sub.2 OMe).sub.2, R.sup.4a is CN, R.sup.4b is H, R.sup.4c is OMe, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --N(c-Pr) (CH.sub.2 CH.sub.2 CN), R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is Me; PA1 a compound of Formula (50) wherein R.sup.3 is --NCH (CH.sub.2 OMe).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Br, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(CH.sub.2 OMe) (CH.sub.2 CH.sub.2 OMe), R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Br, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(CH.sub.2 OMe).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is OMe, R.sup.4d is Me and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --N(CH.sub.2 CH.sub.2 OMe).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is OMe, R.sup.4d is Me and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(Et).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is OMe, R.sup.4d is Me and R.sup.4e is H; PA1 a compound of Formula (50) wherein a compound of Formula (50) wherein R.sup.3 is --N(Et).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is OMe, R.sup.4d is Me and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(CH.sub.2 OMe).sub.2, R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(Et) (CH.sub.2 OMe), R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --N(CH.sub.2 CH.sub.2 OMe).sub.2, R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(CH.sub.2 OMe) (CH.sub.2 CH.sub.2 OMe), R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --N(c-Pr) (CH.sub.2 CH.sub.2 CN), R.sup.4a is Me, R.sup.4b is H, R.sup.4c is OMe, R.sup.4d is Me and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --N(c-Pr) (CH.sub.2 CH.sub.2 CN), R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is (S)--NHCH(CH.sub.2 OMe) (CH.sub.2 CH.sub.2 OMe), R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(CH.sub.2 OMe) (CH.sub.2 CH.sub.2 OMe), R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(Et).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Br, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --N(CH.sub.2 CH.sub.2 OMe).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Br, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NH(CH.sub.2 OMe) (CH.sub.2 -iPr), R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --N(CH.sub.2 CH.sub.2 OMe).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is H, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --N(CH.sub.2 CH.sub.2 OMe).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is NMe.sub.2, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(CH.sub.2 OMe) (n-Pr), R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(CH.sub.2 OEt) (Et), R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(CH.sub.2 OMe) (CH.sub.2 CH.sub.2 OMe), R.sup.4a is Me, R.sup.4b is H, R.sup.4c is NMe.sub.2, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --N(Et).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(Et).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --N(CH.sub.2 CH.sub.2 OMe).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(CH.sub.2 OMe).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --N(Et).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Br, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --N(Et).sub.2, R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(Et).sub.2, R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(Et).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is NMe.sub.2, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is (S)--NHCH(CH.sub.2 OMe) (CH.sub.2 CH.sub.2 OMe), R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(CH.sub.2 OMe) (CH.sub.2 CH.sub.2 OMe), R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is (S)--NHCH(CH.sub.2 OMe) (CH.sub.2 CH.sub.2 OMe), R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(CH.sub.2 OMe) (CH.sub.2 CH.sub.2 OMe), R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --N(c-Pr) (CH.sub.2 CH.sub.2 CN), R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NH(Et) (CH.sub.2 CN), R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --N(Et).sub.2, R.sup.4a is Me, R.sup.4b is Me, R.sup.4c is OMe, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --N(CH.sub.2 CH.sub.2 OMe) (CH.sub.2 CH.sub.2 OH), R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --N(CH.sub.2 CH.sub.2 OMe).sub.2, R.sup.4a is Me, R.sup.4b is Me, R.sup.4c is OMe, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(Et).sub.2, R.sup.4a is Me, R.sup.4b is Me, R.sup.4c is OMe, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --N(CH.sub.2 c-Pr) (n-Pr), R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --N(c-Pr) (CH.sub.2 CH.sub.2 CN), R.sup.4a is Me, R.sup.4b is Me, R.sup.4c is OMe, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH (Et).sub.2, R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is OMe, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --N(Et).sub.2, R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is OMe, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --N(CH.sub.2 CH.sub.2 OMe).sub.2, R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is OMe, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(Et) (CH.sub.2 OMe), R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is OMe, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --N(Et).sub.2, R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is CN, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --N(c-Pr) (CH.sub.2 CH.sub.2 CN), R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is OMe, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (50) wherein R.sup.3 is --NHCH(CH.sub.2 OH).sub.2, R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; and PA1 a compound of Formula (50) wherein R.sup.3 is N(CH.sub.2 CH.sub.2 OMe).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is OMe, R.sup.4d is H and R.sup.4e is H. PA1 Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R.sup.4 substituents, PA1 R.sup.3 is Nr.sup.6a R.sup.7a or OR.sup.7 and PA1 R.sup.1 and R.sup.2 are independently selected from H, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl. PA1 a compound of Formula (51) wherein R.sup.3 is --NHCH(n-Pr).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --NHCH(CH.sub.2 OMe).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --N(CH.sub.2 CH.sub.2 OMe).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --N(c-Pr) (CH.sub.2 CH.sub.2 CN), R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --N(CH.sub.2 CH.sub.2 OMe).sub.2, R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --NHCH(CH.sub.2 OMe).sub.2, R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --NHCH(Et).sub.2, R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --N(Et).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --N(n-Pr) (CH.sub.2 CH.sub.2 CN), R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --N(n-Bu) (CH.sub.2 CH.sub.2 CN), R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --NHCH(n-Pr) (CH.sub.2 OMe), R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --NHCH(Et).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is OMe, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --NHCH(CH.sub.2 OMe).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is OMe, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is (S)--NH(CH.sub.2 CH.sub.2 OMe)CH.sub.2 OMe, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --NH(CH.sub.2 CH.sub.2 OMe)CH.sub.2 OMe, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --N(CH.sub.2 CH.sub.2 OMe).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --NH(Et), R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --NHCH(n-Pr).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --NHCH(CH.sub.2 OMe).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is (S)--NH(CH.sub.2 CH.sub.2 OMe)CH.sub.2 OMe, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --NH(CH.sub.2 CH.sub.2 OMe)CH.sub.2 OMe, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --N(n-Pr) (CH.sub.2 CH.sub.2 CN), R.sup.4a is Me, R.sup.4b is H, R.sup.4c is OMe, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --N(Et).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is OMe, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is (S)--NH(CH.sub.2 CH.sub.2 OMe)CH.sub.2 OMe, R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --NH(CH.sub.2 CH.sub.2 OMe)CH.sub.2 OMe, R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --N(Et).sub.2, R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --N(c-Pr) (CH.sub.2 CH.sub.2 CN), R.sup.4a is Me, R.sup.4b is H, R.sup.4c is OMe, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --N(c-Pr) (CH.sub.2 CH.sub.2 CN), R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --NHCH(n-Pr) (CH.sub.2 OMe), R.sup.4a is Me, R.sup.4b is H, R.sup.4c is OMe, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --NHCH(n-Pr) (CH.sub.2 OMe), R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --NHCH(Et).sub.2, R.sup.4a is Br, R.sup.4b is H, R.sup.4c is OMe, R.sup.4d is OMe and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --NHCH(Et).sub.2, R.sup.4a is Br, R.sup.4b is H, R.sup.4c is OMe, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --N(CH.sub.2 CH.sub.2 OMe).sub.2, R.sup.4a is Br, R.sup.4b is H, R.sup.4c is OMe, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --NHCH(CH.sub.2 OMe).sub.2, R.sup.4a is Br, R.sup.4b is H, R.sup.4c is OMe, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --N(Et).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --N(Et).sub.2, R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is OMe, R.sup.4d is OMe and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --NHCH(Et).sub.2, R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is OMe, R.sup.4d is OMe and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --N(CH.sub.2 CH.sub.2 OMe).sub.2, R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --NHCH(CH.sub.2 OMe).sub.2, R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --N(Pr) (CH.sub.2 CH.sub.2 CN), R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --N(Bu) (Et), R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --NHCH(Et)CH.sub.2 OMe, R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 compound of Formula (51) wherein R.sup.3 is --NHCH(Et).sub.2, R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --NHCH(Et).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --NHCH(Et).sub.2, R.sup.4a is Cl, R.sup.4b is H, R.sup.4c is Me, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --NHCH(Et).sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is Cl, R.sup.4d is H and R.sup.4e is H; PA1 a compound of Formula (51) wherein R.sup.3 is --NEt.sub.2, R.sup.4a is Me, R.sup.4b is H, R.sup.4c is OMe, R.sup.4d is H and R.sup.4e is H; and PA1 a compound of Formula (51) wherein R.sup.3 is --N(Pr) (CH.sub.2 CH.sub.2 CN), R.sup.4a is Me, R.sup.4b is H, R.sup.4c is OMe, R.sup.4d is H and R.sup.4e is H. PA1 Z is N or CR.sup.2 ; PA1 Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl, 3,4-dihydro-1,2-benzopyranyl, tetralinyl, each Ar optionally substituted with 1 to 5 R.sup.4 groups and each Ar is attached to an unsaturated carbon atom; PA1 R.sup.1 is independently selected at each occurrence from H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, halo, CN, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.12 hydroxyalkyl, C.sub.2 -C.sub.12 alkoxyalkyl, C.sub.2 -C.sub.10 cyanoalkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl, NR.sup.9 R.sup.10, C.sub.1 -C.sub.4 alkyl-NR.sup.9 R.sup.10, NR.sup.9 COR.sup.10, OR.sup.11, SH or S(O).sub.n R.sup.12 ; PA1 R.sup.2 is selected from H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl, C.sub.1 -C.sub.4 hydroxyalkyl, halo, CN, --NR.sup.6 R.sup.7, NR.sup.9 COR.sup.10, --NR.sup.6 S(O).sub.n R.sup.7, S(O).sub.n NR.sup.6 R.sup.7, C.sub.1 -C.sub.4 haloalkyl, --OR.sup.7, SH or --S(O).sub.n R.sup.12 ; PA1 R.sup.3 is selected from: PA1 R.sup.4 is independently selected at each occurrence from: C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, NO.sub.2, halo, CN, C.sub.1 -C.sub.4 haloalkyl, NR.sup.6 R.sup.7, NR.sup.8 COR.sup.7, NR.sup.8 CO.sub.2 R.sup.7, COR.sup.7, OR.sup.7, CONR.sup.6 R.sup.7, CO(NOR.sup.9)R.sup.7, CO.sub.2 R.sup.7, or S(O).sub.n R.sup.7, where each such C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.3 -C.sub.6 cycloalkyl and C.sub.4 -C.sub.12 cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.4 alkyl, NO.sub.2, halo, CN, NR.sup.6 R.sup.7, NR.sup.8 COR.sup.7, NR.sup.8 CO.sub.2 R.sup.7, COR.sup.7 OR.sup.7, CONR.sup.6 R.sup.7, CO.sub.2 R.sup.7, CO(NOR.sup.9)R.sup.7, or S(O).sub.n R.sup.7 ; PA1 R.sup.6, R.sup.7, R.sup.6a and R.sup.7a are independently selected at each occurrence from: PA1 alternatively, NR.sup.6 R.sup.7 and NR.sup.6a R.sup.7a are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1--3 C.sub.1 -C.sub.4 alkyl groups; PA1 R.sup.8 is independently selected at each occurrence from H or C.sub.1 -C.sub.4 alkyl; PA1 R.sup.9 and R.sup.10 are independently selected at each occurrence from H, C.sub.1 -C.sub.4 alkyl, or C.sub.3 -C.sub.6 cycloalkyl; PA1 R.sup.11 is selected from H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 haloalkyl, or C.sub.3 -C.sub.6 cycloalkyl; PA1 R.sup.12 is C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 haloalkyl; PA1 R.sup.13 is selected from C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.2 -C.sub.8 alkoxyalkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, aryl, aryl(C.sub.1 -C.sub.4 alkyl)-, heteroaryl or heteroaryl(C.sub.1 -C.sub.4 alkyl)-; PA1 R.sup.14 is selected from C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, C.sub.3 -C.sub.10 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, or C.sub.4 -C.sub.12 cycloalkylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.15, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.15, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.15, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, and C.sub.1 -C.sub.6 alkylthio, C.sub.1 -C.sub.6 alkylsulfinyl and C.sub.1 -C.sub.6 alkylsulfonyl; PA1 R.sup.15 and R.sup.16 are independently selected at each occurrence from H, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.4 -C.sub.16 cycloalkylalkyl, except that for S(O).sub.n R.sup.15, R.sup.15 cannot be H; PA1 aryl is phenyl or naphthyl, each optionally substituted with 1 to 5 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.15, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.15, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.15, NR.sup.16 R.sup.15 and CONR.sup.16 R.sup.15 ; PA1 heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, 2,3-dihydrobenzothienyl or 2,3-dihydrobenzofuranyl, each being optionally substituted with 1 to 5 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.15, --COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.15, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.15, NR.sup.16 R.sup.15, and CONR.sup.16 R.sup.15 ; PA1 heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 5 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.15, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.15, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.15, NR.sup.15 R.sup.16, and CONR.sup.16 R.sup.15 ; PA1 n is independently at each occurrence 0, 1 or 2; PA1 with the proviso that when Z is CR.sup.2, then R.sup.3 is not NR.sup.6 R.sup.7, NR.sup.6a R.sup.7a or OR.sup.7. PA1 Z is N or CR.sup.2 ; PA1 Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl, 3,4-dihydro-1,2-benzopyranyl, tetralinyl, each Ar optionally substituted with 1 to 5 R.sup.4 groups and each Ar is attached to an unsaturated carbon atom; PA1 R.sup.1 is independently selected at each occurrence from H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, halo, CN, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 C.sub.12 hydroxyalkyl, C.sub.2 -C.sub.12 alkoxyalkyl, C.sub.2 -C.sub.10 cyanoalkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl, NR.sup.9 R.sup.10, C.sub.1 -C.sub.4 alkyl-NR.sup.9 R.sup.10, NR.sup.9 COR.sup.10, OR.sup.11, SH or S(O).sub.n R.sup.12 ; PA1 R.sup.2 is selected from H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl, C.sub.1 -C.sub.4 hydroxyalkyl, halo, CN, --NR.sup.6 R.sup.7, NR.sup.9 COR.sup.10, --NR.sup.6 S(O).sub.n R.sup.7, S(O).sub.n NR.sup.6 R.sup.7, C.sub.1 -C.sub.4 haloalkyl, --OR.sup.7, SH or --S(O).sub.n R.sup.12 ; PA1 R.sup.3 is selected from: PA1 R.sup.4 is independently selected at each occurrence from: C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, NO.sub.2, halo, CN, C.sub.1 -C.sub.4 haloalkyl, NR.sup.6 R.sup.7, NR.sup.8 COR.sup.7, NR.sup.8 CO.sub.2 R.sup.7, COR.sup.7, OR.sup.7, CONR.sup.6 R.sup.7, CO(NOR.sup.9)R.sup.7, CO.sub.2 R.sup.7, or S(O).sub.n R.sup.7, where each such C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.3 -C.sub.6 cycloalkyl and C.sub.4 -C.sub.12 cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.4 alkyl, NO.sub.2, halo, CN, NR.sup.6 R.sup.7, NR.sup.8 COR.sup.7, NR.sup.8 CO.sub.2 R.sup.7, COR.sup.7, OR.sup.7, CONR.sup.6 R.sup.7, CO.sub.2 R.sup.7, CO(NOR.sup.9)R.sup.7, or S(O).sub.n R.sup.7 ; PA1 R.sup.6, R7, R.sup.6a and R.sup.7a are independently selected at each occurrence from: PA1 alternatively, NR.sup.6 R.sup.7 and NR.sup.6a R.sup.7a are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C.sub.1 -C.sub.4 alkyl groups; PA1 R.sup.8 is independently selected at each occurrence from H or C.sub.1 -C.sub.4 alkyl; PA1 R.sup.9 and R.sup.10 are independently selected at each occurrence from H, C.sub.1 -C.sub.4 alkyl, or C.sub.3 -C.sub.6 cycloalkyl; PA1 R.sup.11 is selected from H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 haloalkyl, or C.sub.3 -C.sub.6 cycloalkyl; PA1 R.sup.12 is C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 haloalkyl; PA1 R.sup.13 is selected from C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.2 -C.sub.8 alkoxyalkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, aryl, aryl(C.sub.1 -C.sub.4 alkyl)-, heteroaryl or heteroaryl(C.sub.1 -C.sub.4 alkyl)-; PA1 R.sup.14 is selected from C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, C.sub.3 -C.sub.10 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, or C.sub.4 -C.sub.12 cycloalkylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.15 COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.15, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.15, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, and C.sub.1 -C.sub.6 alkylthio, C.sub.1 -C.sub.6 alkylsulfinyl and C.sub.1 -C.sub.6 alkylsulfonyl; PA1 R.sup.15 and R.sup.16 are independently selected at each occurrence from H, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.4 -C.sub.16 cycloalkylalkyl, except that for S(O).sub.n R.sup.15, R.sup.15 cannot be H; PA1 aryl is phenyl or naphthyl, each optionally substituted with 1 to 5 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.15, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.15, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.15, NR.sup.16 R.sup.15, and CONR.sup.16 R.sup.15 ; PA1 heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, 2,3-dihydrobenzothienyl or 2,3-dihydrobenzofuranyl, each being optionally substituted with 1 to 5 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.15, --COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.15, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.15, NR.sup.16 R.sup.15, and CONR.sup.16 R.sup.15 ; PA1 heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 5 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.15, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.15, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.15, NR.sup.15 R.sup.16, and CONR.sup.16 R.sup.15 ; PA1 n is independently at each occurrence 0, 1 or 2; PA1 with the provisos that: PA1 R.sup.6a is independently selected from: PA1 R.sup.7a is independently selected at each occurrence from: PA1 alternatively, NR.sup.6 R.sup.7 and NR.sup.6a R.sup.7a are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C.sub.1 -C.sub.4 alkyl groups. PA1 R.sup.6a and R.sup.7a are identical and are selected from: PA1 R.sup.6a is selected from: PA1 R.sup.7a is selected from: PA1 one of R.sup.6a and R.sup.7a is selected from: PA1 and the other of R.sup.6a and R.sup.7a is unsubstituted C.sub.1 -C.sub.4 alkyl. PA1 Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R.sup.4 substituents, PA1 R.sup.1 and R.sup.2 are independently selected from H, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl. PA1 Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R.sup.4 substituents, PA1 R.sup.1 and R.sup.2 are independently selected from H, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl. PA1 Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R.sup.4 substituents, PA1 R.sup.1 and R.sup.2 are independently selected from H, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl. PA1 Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R.sup.4 substituents, PA1 R.sup.1 and R.sup.2 are independently selected from H, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl. PA1 Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R.sup.4 substituents, PA1 R.sup.1 and R.sup.2 are independently selected from H, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl. PA1 Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R.sup.4 substituents, PA1 R.sup.1 and R.sup.2 are independently selected from H, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl. PA1 R.sup.6a and R.sup.7a are independently H or C.sub.1 -C.sub.10 alkyl, each such C.sub.1 -C.sub.10 alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.13, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.13, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, R.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, aryl, heteroaryl or heterocyclyl.
EP 0 594 149 (Ostuka, 1994) discloses pyrazolotriazine and pyrazolopyrimidine compounds of the formula ##STR3##
U.S. Pat. No. 3,910,907 (ICI, 1975) discloses pyrazolotriazines of the formula: ##STR4##
U.S. Pat. No. 3,995,039 discloses pyrazolotriazines of the formula: ##STR5##
U.S. Pat. No. 5,137,887 discloses pyrazolotriazines of the formula ##STR6##
U.S. Pat. No. 4,892,576 discloses pyrazolotriazines of the formula ##STR7##
U.S. Pat. No. 5,484,760 and WO 92/10098 discloses herbicidal compositions containing, among other things, a herbicidal compound of the formula ##STR8##
where X, Y and Z are H, alkyl, acyl, etc. and D is O or S. PA2 H, OR.sup.7, SH, S(O).sub.n R.sup.13, COR.sup.7, CO.sub.2 R.sup.7, OC(O)R.sup.13, NR.sup.8 COR.sup.7, N(COR.sup.7).sub.2, NR.sup.8 CONR.sup.6 R.sup.7, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.6 R.sup.7, NR.sup.6a R.sup.7a, N(OR.sup.7)R.sup.6, CONR.sup.6 R.sup.7, aryl, heteroaryl and heterocyclyl, or PA2 C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.5 -C.sub.8 cycloalkenyl, C.sub.4 -C.sub.12 cycloalkylalkyl or C.sub.6 -C.sub.10 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.13, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.13, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, aryl, heteroaryl and heterocyclyl; PA2 C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, NO.sub.2, halo, CN, C.sub.1 -C.sub.4 haloalkyl, NR.sup.6 R.sup.7, NR.sup.8 COR.sup.7, NR.sup.8 CO.sub.2 R.sup.7, COR.sup.7, OR.sup.7, CONR.sup.6 R.sup.7, CO(NOR.sup.9)R.sup.7, CO.sub.2 R.sup.7, or S(O).sub.n R.sup.7, where each such C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.3 -C.sub.6 cycloalkyl and C.sub.4 -C.sub.12 cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.4 alkyl, NO.sub.2, halo, CN, NR.sup.6 R.sup.7, NR.sup.8 COR.sup.7, NR.sup.8 CO.sub.2 R.sup.7, COR.sup.7 OR.sup.7, CONR.sup.6 R.sup.7, CO.sub.2 R.sup.7, CO(NOR.sup.9)R.sup.7, or S(O).sub.n R.sup.7 ; PA2 H, PA2 C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, C.sub.3 -C.sub.10 alkynyl, C.sub.1 -C.sub.10 haloalkyl with 1-10 halogens, C.sub.2 -C.sub.8 alkoxyalkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, C.sub.5 -C.sub.10 cycloalkenyl, or C.sub.6 -C.sub.14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.13, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.13, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, aryl, heteroaryl or heterocyclyl, PA2 aryl, aryl(C.sub.1 -C.sub.4 alkyl), heteroaryl, heteroaryl(C.sub.1 -C.sub.4 alkyl), heterocyclyl or heterocyclyl(C.sub.1 -C.sub.4 alkyl); PA2 H, OR.sup.7, SH, S(O).sub.n R.sup.13, COR.sup.7, CO.sub.2 R.sup.7, OC(O)R.sup.13, NR.sup.8 COR.sup.7, N(COR.sup.7).sub.2, NR.sup.8 CONR.sup.6 R.sup.7, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.6 R.sup.7, NR.sup.6a R.sup.7a, N(OR.sup.7)R.sup.6, CONR.sup.6 R.sup.7, aryl, heteroaryl and heterocyclyl, or PA2 C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.5 -C.sub.8 cycloalkenyl, C.sub.4 -C.sub.12 cycloalkylalkyl or C.sub.6 -C.sub.10 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.13, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.13, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, aryl, heteroaryl and heterocyclyl; PA2 H, PA2 C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, C.sub.3 -C.sub.10 alkynyl, C.sub.1 -C.sub.10 haloalkyl with 1-10 halogens, C.sub.2 -C.sub.8 alkoxyalkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, C.sub.5 -C.sub.10 cycloalkenyl, or C.sub.6 -C.sub.14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.13, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.13, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, aryl, heteroaryl or heterocyclyl, PA2 aryl, aryl(C.sub.1 -C.sub.4 alkyl), heteroaryl, heteroaryl(C.sub.1 -C.sub.4 alkyl), heterocyclyl or heterocyclyl(C.sub.1 -C.sub.4 alkyl), PA2 (1) when A is N, Z is CR.sup.2, R.sup.2 is H, R.sup.3 is --OR.sup.7 or --OCOR.sup.13, and R.sup.7 is H, then R.sup.1 is not H, OH or SH; PA2 (2) when A is N, Z is CR.sup.2, R.sup.1 is CH.sub.3 or C.sub.2 H.sub.5, R.sup.2 is H, and R.sup.3 is OH, H, CH.sub.3, C.sub.2 H.sub.5, C.sub.6 H.sub.5, n-C.sub.3 H.sub.7, i-C.sub.3 H.sub.7, SH, SCH.sub.3, NHC.sub.4 H.sub.9, or N(C.sub.2 H.sub.5).sub.2, then Ar is not phenyl or m-CH.sub.3 -phenyl; PA2 (3) when A is N, Z is CR.sup.2, R.sup.2 is H, and Ar is pyridyl, pyrimidinyl or pyrazinyl, and R.sup.3 is NR.sup.6a R.sup.7a, then R.sup.6a and R.sup.7a are not H or alkyl; PA2 (4) when A is N, Z is CR.sup.2, and R.sup.2 is SO.sub.2 NR.sup.6 R.sup.7, then R.sup.3 is not OH or SH; PA2 (5) when A is CR and Z is CR.sup.2, then R.sup.2 is not --NR.sup.6 SO.sub.2 R.sup.7 or --SO.sub.2 NR.sup.6 R.sup.7 ; PA2 (6) when A is N, Z is CR.sup.2 and R.sup.2 is --NR.sup.6 SO.sub.2 R.sup.7 or --SO.sub.2 NR.sup.6 R.sup.7, then R.sup.3 is not OH or SH; PA2 (7) when A is N, Z is CR.sup.2, R.sup.1 is methyl or ethyl, R.sup.2 is H, and R.sup.3 is H, OH, CH.sub.3, C.sub.2 H.sub.5, C.sub.6 H.sub.5, n-C.sub.3 H.sub.7, iso-C.sub.3 H.sub.7, SH, SCH.sub.3, NH(n-C.sub.4 H.sub.9), or N(C.sub.2 H.sub.5).sub.2, then Ar is not unsubstituted phenyl or m-methylphenyl; PA2 (8) when A is CR, Z is CR.sup.2, R.sup.2 is H, phenyl or alkyl, R.sup.3 is NR.sup.8 COR.sup.7 and Ar is phenyl or phenyl substituted with phenylthio, then R.sup.7 is not aryl, aryl(C.sub.1 -C.sub.4 alkyl), heteroaryl, heteroaryl(C.sub.1 -C.sub.4 alkyl), heterocyclyl or heterocycly(C.sub.1 -C.sub.4 alkyl); PA2 (9) when A is CR, Z is CR.sup.2, R.sup.2 is H or alkyl, Ar is phenyl, and R.sup.3 is SR.sup.13 or NR.sup.6a R.sup.7a, then R.sup.13 is not aryl or heteroaryl and R.sup.6a and R.sup.7a are not H or aryl; or PA2 (10) when A is CH, Z is CR.sup.2, R.sup.1 is OR.sup.11, R.sup.2 is H, R.sup.3 is OR.sup.7, and R.sup.7 and R.sup.11 are both H, then Ar is not phenyl, p-Br-phenyl, p-Cl-phenyl, p-NHCOCH.sub.3 -phenyl, p-CH.sub.3 -phenyl, pyridyl or naphthyl; PA2 (11) when A is CH, Z is CR.sup.2, R.sup.2 is H, Ar is unsubstituted phenyl, and R.sup.3 is CH.sub.3, C.sub.2 H.sub.5, CF.sub.3 or C.sub.6 H.sub.4 F, then R.sub.1 is not CF.sub.3 or C.sub.2 F.sub.5 ; PA2 (12) when A is CR, R is H, Z is CR.sup.2, R.sup.2 is OH, and R.sup.1 and R.sup.3 are H, then Ar is not phenyl; PA2 (13) when A is CR, R is H, Z is CR.sup.2, R.sup.2 is OH or NH.sub.2, R.sup.1 and R.sup.3 are CH.sub.3, then Ar is not 4-phenyl-3-cyano-2-aminopyrid-2-yl. PA2 H, OR.sup.7, SH, S(O).sub.n R.sup.13, COR.sup.7.sub.1, CO.sub.2 R.sup.7, OC(O)R.sup.13, NR.sup.8 COR.sup.7, N(COR.sup.7).sub.2, NR.sup.8 CONR.sup.6 R.sup.7, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.6 R.sup.7, NR.sup.6a R.sup.7a, N(OR.sup.7)R.sup.6, CONR.sup.6 R.sup.7, aryl, heteroaryl and heterocyclyl, or PA2 C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.5 -C.sub.8 cycloalkenyl, C.sub.4 -C.sub.12 cycloalkylalkyl or C.sub.6 -C.sub.10 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.13, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.13, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, aryl, heteroaryl and heterocyclyl; PA2 H, PA2 C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, C.sub.3 -C.sub.10 alkynyl, C.sub.1 -C.sub.10 haloalkyl with 1-10 halogens, C.sub.2 -C.sub.8 alkoxyalkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, C.sub.5 -C.sub.10 cycloalkenyl, or C.sub.6 -C.sub.14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.13, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.13, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, aryl, heteroaryl or heterocyclyl, PA2 aryl, aryl(C.sub.1 -C.sub.4 alkyl), heteroaryl, heteroaryl(C.sub.1 -C.sub.4 alkyl), heterocyclyl or heterocyclyl(C.sub.1 -C.sub.4 alkyl); PA2 H, OR.sup.7, SH, S(O).sub.n R.sup.13, COR.sup.7, CO.sub.2 R.sup.7, OC(O)R.sup.13, NR.sup.8 COR.sup.7, N(COR.sup.7).sub.2, NR.sup.8 CONR.sup.6 R.sup.7, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.6 R.sup.7, NR.sup.6a R.sup.7a, N(OR.sup.7)R.sup.6, CONR.sup.6 R.sup.7, aryl, heteroaryl and heterocyclyl, or PA2 C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.5 -C.sub.8 cycloalkenyl, C.sub.4 -C.sub.12 cycloalkylalkyl or C.sub.6 -C.sub.10 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.13, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.13, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, aryl, heteroaryl and heterocyclyl; PA2 H, PA2 C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, C.sub.3 -C.sub.10 alkynyl, C.sub.1 -C.sub.10 haloalkyl with 1-10 halogens, C.sub.2 -C.sub.8 alkoxyalkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, C.sub.5 -C.sub.10 cycloalkenyl, or C.sub.6 -C.sub.14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.13, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.13, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, aryl, heteroaryl or heterocyclyl, PA2 aryl, aryl(C.sub.1 -C.sub.4 alkyl), heteroaryl, heteroaryl(C.sub.1 -C.sub.4 alkyl), heterocyclyl or heterocyclyl(C.sub.1 -C.sub.4 alkyl), PA2 (1) when Z is CR.sup.2 and R.sup.2 is H and R.sup.3 is OCOR.sup.13 and R.sup.7 is H, then R.sup.1 is not H, OH or SH; PA2 (2) when Z is CR.sup.2 and R.sup.1 is CH.sub.3 or C.sub.2 H.sub.5 and R.sup.2 is H, and R.sup.3 is H, CH.sub.3, C.sub.2 H.sub.5, C.sub.6 H.sub.5, n-C.sub.3 H.sub.7, i-C.sub.3 H.sub.7, SH or SCH.sub.3, then Ar is not phenyl or m-CH.sub.3 -phenyl; PA2 (3) when Z is CR.sup.2 and R.sup.2 is --NR.sup.6 SO.sub.2 R.sup.7 or --SO.sub.2 NR.sup.6 R.sup.7, then R.sup.3 is not SH; and PA2 (4) when Z is CR.sup.2, then R.sup.3 is not NR.sup.6 R.sup.7, NR.sup.6a R.sup.7a or OR.sup.7. PA2 H, PA2 C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, C.sub.3 -C.sub.10 alkynyl, C.sub.1 -C.sub.10 haloalkyl with 1-10 halogens, C.sub.2 -C.sub.8 alkoxyalkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, C.sub.5 -C.sub.10 cycloalkenyl, or C.sub.6 -C.sub.14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.13, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.13, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, aryl, heteroaryl or heterocyclyl, PA2 aryl, aryl(C.sub.1 -C.sub.4 alkyl)-, heteroaryl, heteroaryl(C.sub.1 -C.sub.4 alkyl)-, heterocyclyl or heterocyclyl(C.sub.1 -C.sub.4 alkyl)-; and PA2 H, PA2 C.sub.5 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, C.sub.3 -C.sub.10 alkynyl, C.sub.1 -C.sub.10 haloalkyl with 1-10 halogens, C.sub.2 -C.sub.8 alkoxyalkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, C.sub.5 -C.sub.10 cycloalkenyl, or C.sub.6 -C.sub.14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.13, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.13, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, aryl, heteroaryl or heterocyclyl, PA2 aryl, aryl(C.sub.1 -C.sub.4 alkyl), heteroaryl, heteroaryl(C.sub.1 -C.sub.4 alkyl), heterocyclyl or heterocyclyl(C.sub.1 -C.sub.4 alkyl); PA2 C.sub.1 -C.sub.4 alkyl or C.sub.3 -C.sub.6 cycloalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.13, --COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.13, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, aryl, heteroaryl or heterocyclyl, and PA2 aryl or heteroaryl. PA2 H, PA2 C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, C.sub.3 -C.sub.10 alkynyl, C.sub.1 -C.sub.10 haloalkyl with 1-10 halogens, C.sub.2 -C.sub.8 alkoxyalkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 --C.sub.12 cycloalkylalkyl, C.sub.5 -C.sub.10 cycloalkenyl, or C.sub.6 -C.sub.14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.13, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.13, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, aryl, heteroaryl or heterocyclyl, PA2 aryl, aryl(C.sub.1 -C.sub.4 alkyl), heteroaryl, heteroaryl(C.sub.1 -C.sub.4 alkyl), heterocyclyl or heterocyclyl(C.sub.1 -C.sub.4 alkyl); PA2 C.sub.1 -C.sub.4 alkyl and each such C.sub.1 -C.sub.4 alkyl is substituted with 1-3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.13, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.13, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, aryl, heteroaryl or heterocyclyl. PA2 C.sub.3 -C.sub.6 cycloalkyl, each such C.sub.3 -C.sub.6 cycloalkyl optionally substituted with 1-3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, OR.sup.15, SH, S(O).sub.n R.sup.13, COR.sup.15, CO.sub.2 R.sup.15, OC(O)R.sup.13, NR.sup.8 COR.sup.15, N(COR.sup.15).sub.2, NR.sup.8 CONR.sup.16 R.sup.15, NR.sup.8 CO.sub.2 R.sup.13, NR.sup.16 R.sup.15, CONR.sup.16 R.sup.15, aryl, heteroaryl or heterocyclyl, PA2 aryl, PA2 heteroaryl or PA2 heterocyclyl,
U.S. Pat. No. 3,910,907 and Senga et al., J. Med. Chem., 1982, 25, 243-249, disclose triazolotriazines cAMP phosphodiesterase inhibitors of the formula ##STR10##
WO95/35298 (Otsuka, 1995) discloses pyrazolopyrimidines and states that they are useful as analgesics. The compounds are represented by the formula ##STR11##
EP 0 591 528 (Otsuka, 1991) discloses anti-inflammatory use of pyrazolopyrimidines represented by the formula ##STR12##
Springer et al, J. Med. Chem., 1976, vol. 19, no. 2, 291-296 and Springer U.S. Pat. Nos. 4,021,556 and 3,920,652 disclose pyrazolopyrimidines of the formula ##STR13##
Joshi et al., J. Prakt. Chemie, 321, 2, 1979, 341-344, discloses compounds of the formula ##STR14##
Maquestiau et al., Bull. Soc. Belg., vol.101, no. 2, 1992, pages 131-136 discloses a pyrazolo[1,5-a]pyrimidine of the formula ##STR15##
Ibrahim et al., Arch. Pharm. (weinheim) 320, 487-491 (1987) discloses pyrazolo[1,5-a]pyrimidines of the formula ##STR16##
Other references which disclose azolopyrimidines inclued EP 0 511 528 (Otsuka, 1992), U.S. Pat. No. 4,997,940 (Dow, 1991), EP 0 374 448 (Nissan, 1990), U.S. Pat. No. 4,621,556 (ICN, 1997), EP 0 531 901 (Fujisawa, 1993), U.S. Pat. No. 4,567,263 (BASF, 1986), EP 0 662 477 (Isagro, 1995), U.S. Pat. No. DE 4 243 279 (Bayer, 1994), U.S. Pat. No. 5,397,774 (Upjohn, 1995), EP 0 521 622 (Upjohn, 1993), WO 94/109017 (Upjohn, 1994), J. Med. Chem., 24, 610-613 ( 1981), and J. Het. Chem., 22, 601 ( 1985).